Livtencity
maribavir
Species
MonkeyRatMouse
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (plus 13-week mouse)
“Pivotal repeat-dose toxicology evaluations for maribavir included good laboratory practice studies of up to 52 weeks duration in monkeys, 26 weeks duration in rats and 13 weeks duration in mice”
Why that species
Main human metabolite VP 44469 present in mice, rats and monkeys; common toxicity species
“Mice, rats and monkeys were chosen for single and repeat-dose toxicity studies because the main human metabolite of maribavir, VP 44469 was present in all of them and these species are common species for toxicity testing.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 52-week monkey study, 2 males at 400/300 mg/kg/day (two dose levels indicate dose adjustment during the study) and 1 male at 200 mg/kg/day were euthanized in extremis.”
Species: general tox
Cynomolgus monkey (52-week), rat (26-week) and mouse (13-week)
“Pivotal repeat-dose toxicology evaluations for maribavir included good laboratory practice studies of up to 52 weeks duration in monkeys, 26 weeks duration in rats and 13 weeks duration in mice”
Species: DART
Rat (combined fertility/EFD; pre/postnatal) and rabbit (EFD)
“No significant toxicological effects on embryo-fetal growth or development were observed in rabbits when maribavir was administered at oral doses up to 100 mg/kg/day from GD 8 to 20, at exposures approximately half the human exposure at the RHD. In the pre-and post-natal developmental toxicity study, maribavir was administered to pregnant rats at oral doses of 50, 150, or 400 mg/kg/day from GD 7 to post-natal day (PND) 21.”
Species: carcinogenicity
Mouse (2-year) and rat (2-year)
“Two-year carcinogenicity studies were conducted in mice and rats administered oral doses up to 150 and 100 mg/kg/day, respectively.”
Surrogate used in
No surrogate molecule; in vivo antiviral pharmacology used transplanted human tissue or surrogate animal viral strains
“In vivo pharmacodynamics effects on HCMV were analysed in different animal models (transplanted human tissue or surrogate animal viral strains) in comparison to ganciclovir a two other benzimidazole nucleosides.”
Study lengthopen answer page →
Longest pivotal study
52 (52-week monkey)
“Pivotal repeat-dose toxicology evaluations for maribavir included good laboratory practice studies of up to 52 weeks duration in monkeys, 26 weeks duration in rats and 13 weeks duration in mice”
Pivotal GLP studies
52-week cynomolgus monkey, 26-week rat and 13-week mouse GLP studies
“Pivotal repeat-dose toxicology evaluations for maribavir included good laboratory practice studies of up to 52 weeks duration in monkeys, 26 weeks duration in rats and 13 weeks duration in mice”
Route in tox
Oral (once daily in rodents, twice daily in monkeys)
“Maribavir was applied orally once a day to mice and rats, and according to the clinical treatment schedule twice a day to monkeys.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and in vivo rat micronucleus; mutagenic without metabolic activation in mouse lymphoma assay; overall not genotoxic
“Although maribavir demonstrated mutagenic potential in the absence of metabolic activation in the mouse lymphoma assay, given the negative results of the in vivo rat micronucleus assay and the negative bacterial mutation assay, the weight of evidence indicates that maribavir does not exhibit genotoxic potential.”
Carcinogenicity
Mouse: hemangiosarcoma in males at 150 mg/kg/day; rat: not carcinogenic (exposures below human RHD)
“Maribavir was not carcinogenic in rats at any dose tested, corresponding to maribavir exposures less than human exposure at the RHD. At 150 mg/kg/day in male mice only, an increased incidence of hemangiosarcoma and combined hemangioma/ hemangiosarcoma was observed across multiple tissues at exposures less than the human exposure at the RHD.”
Reproductive & developmental
Fewer viable fetuses, more early resorptions and post-implantation loss at ≥100 mg/kg/day (about half human exposure)
“A decrease in the number of viable fetuses, and increase in early resorptions and post-implantation losses were observed at ≥100 mg/kg/day (at exposures approximately half the human exposure at the RHD).”
Safety pharmacology
No hERG effect up to 1500 µg/mL, >4000-fold the clinical unbound Cmax
“Maribavir had no effect on the hERG current at concentrations of up to 1500 µg/mL (measured concentration 1250 µg/mL), providing a wide safety margin of more than 4000-fold the anticipated clinical plasma unbound Cmax of 0.344 µg/mL (0.91 µM), at the maximum proposed clinical dose of 400 mg BID.”
Genotox: Ames
Negative
“Maribavir was negative in a bacterial mutation assay and the in vivo rat bone marrow micronucleus assay.”
Genotox: in vitro mammalian
Mouse lymphoma assay: positive without metabolic activation, equivocal with activation
“Maribavir was positive in the absence of metabolic activation in the mouse lymphoma assay, and the results were equivocal in the presence of metabolic activation.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Maribavir was negative in a bacterial mutation assay and the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
2-year mouse (up to 150 mg/kg/day) and 2-year rat (up to 100 mg/kg/day)
“Two-year carcinogenicity studies were conducted in mice and rats administered oral doses up to 150 and 100 mg/kg/day, respectively.”
Carcinogenicity timing
2-year mouse and 2-year rat completed before the marketing application
“Two-year carcinogenicity studies were conducted in mice and rats administered oral doses up to 150 and 100 mg/kg/day, respectively.”
hERG / QT
No hERG effect up to 1500 µg/mL; >4000-fold unbound clinical Cmax
“Maribavir had no effect on the hERG current at concentrations of up to 1500 µg/mL (measured concentration 1250 µg/mL), providing a wide safety margin of more than 4000-fold the anticipated clinical plasma unbound Cmax of 0.344 µg/mL (0.91 µM), at the maximum proposed clinical dose of 400 mg BID.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Livtencity don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Regenerative anemia and gastrointestinal effects in the 52-week monkey and 26-week rat studies (FDA integrated review, p. 75)
NOAEL / key findings
Regenerative anemia and gastrointestinal effects in the 52-week monkey and 26-week rat studies
“The major findings in the 52-week study in monkeys and 26-week study in rats were regenerative anemia and gastrointestinal effects”
Risksopen answer page →
Immune & cytokine safety
Not immunotoxic in rats up to 100 mg/kg/day
“Maribavir was not immunotoxic in rats at up to 100 mg/kg/day.”
Biodistribution & persistence
Melanin binding: uveal tract radioactivity ~6-fold higher in pigmented rats, retained beyond 504 h
“In pigmented rats, concentrations of radioactivity in the uveal tract were approximately 6-fold higher than those observed for albino rats, and were measurable through the last timepoint, indicating retention of DRM beyond 504 hours postdose.”
Modality-specific risk
Low or no exposure margins: NOAEL/LOAEL exposures below human exposure at the recommended dose
“The exposures at the no observed adverse effect levels/lowest observed adverse effect levels in the 52-week monkey study, 26-week rat study, and 13-week mouse study were less than the human exposures at the recommended human dose (RHD).”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Risk of Reduced Antiviral Activity When Coadministered with Ganciclovir and Valganciclovir
- Virologic Failure During Treatment and Relapse Post-Treatment
- Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Livtencity don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Regenerative anemia and gastrointestinal effects in the 52-week monkey and 26-week rat studies (FDA integrated review, p. 75)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week cynomolgus monkey (oral gavage) with 8-week recovery
“Following 52 weeks of dosing, all surviving main group animals in the control, 100, and 200 mg/kg/day groups were euthanized. Recovery animals, 2/sex in the control group and 1 male and 2 females in the 200 mg/kg/day dose group, were maintained off dose for an 8-week recovery period.”
Pivotal GLP studies
52-week cynomolgus monkey, 26-week rat and 13-week mouse GLP studies
“Pivotal repeat-dose toxicology evaluations for maribavir included good laboratory practice studies of up to 52 weeks duration in monkeys, 26 weeks duration in rats and 13 weeks duration in mice”
DART package
Species: DART
Rat (combined fertility/EFD; pre/postnatal) and rabbit (EFD)
“No significant toxicological effects on embryo-fetal growth or development were observed in rabbits when maribavir was administered at oral doses up to 100 mg/kg/day from GD 8 to 20, at exposures approximately half the human exposure at the RHD. In the pre-and post-natal developmental toxicity study, maribavir was administered to pregnant rats at oral doses of 50, 150, or 400 mg/kg/day from GD 7 to post-natal day (PND) 21.”
Reproductive & developmental
Fewer viable fetuses, more early resorptions and post-implantation loss at ≥100 mg/kg/day (about half human exposure)
“A decrease in the number of viable fetuses, and increase in early resorptions and post-implantation losses were observed at ≥100 mg/kg/day (at exposures approximately half the human exposure at the RHD).”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In the pre-and postnatal developmental toxicity study maribavir was administered to pregnant rats at oral doses of 50, 150, or 400 mg/kg/day from GD 7 to postnatal day (PND) 21.”
Carcinogenicity
Species: carcinogenicity
Mouse (2-year) and rat (2-year)
“Two-year carcinogenicity studies were conducted in mice and rats administered oral doses up to 150 and 100 mg/kg/day, respectively.”
Carcinogenicity model
2-year mouse (up to 150 mg/kg/day) and 2-year rat (up to 100 mg/kg/day)
“Two-year carcinogenicity studies were conducted in mice and rats administered oral doses up to 150 and 100 mg/kg/day, respectively.”
Carcinogenicity timing
2-year mouse and 2-year rat completed before the marketing application
“Two-year carcinogenicity studies were conducted in mice and rats administered oral doses up to 150 and 100 mg/kg/day, respectively.”
Safety marginopen answer page →
Safety margin at NOAEL
26-week rat NOAEL 25 mg/kg/day: ~0.1x total (0.5x unbound) human AUC; no NOAEL in 52-week monkey
“The NOAEL was set at 25 mg/kg/day resulting in exposures below human therapeutic exposures for total (approximately 0.1-times) and free unbound (approximately 0.5-times) maribavir based on AUC.”
NOAEL / key findings
Regenerative anemia and gastrointestinal effects in the 52-week monkey and 26-week rat studies
“The major findings in the 52-week study in monkeys and 26-week study in rats were regenerative anemia and gastrointestinal effects”
Efficacy evidenceopen answer page →
Efficacy evidence
In vivo HCMV models using transplanted human tissue or surrogate animal viral strains, compared with ganciclovir
“In vivo pharmacodynamics effects on HCMV were analysed in different animal models (transplanted human tissue or surrogate animal viral strains) in comparison to ganciclovir a two other benzimidazole nucleosides.”
Why that model
Strict species specificity of HCMV; no animal model duplicates human infection; drug sensitivity differs for animal CMVs
“Of note, the strict species specificity of HCMV makes studying this virus in an animal model challenging. No animal model perfectly duplicates the human infection.”
Reviewer's view of the efficacy data
FDA: nonclinical biochemical and cell culture virology data support effectiveness against HCMV
“The nonclinical data support the effectiveness of maribavir for the treatment of human cytomegalovirus (HCMV) and include the following findings:”
Flexibilityopen answer page →
Flexibility accepted
GLPAcceptedBeyond the letter
In vivo safety pharmacology studies not GLP-compliant (conducted before ICH S7A)
Why: Studies predated ICH S7A; GLP-compliant toxicity studies and clinical studies available · Weight of evidence · Human data
“Considering that the in vivo safety pharmacology studies have been performed prior to introduction of the ICH S7A guideline and in view of the available GLP-compliant single-and repeated dose toxicity studies and the clinical studies, the lack of GLP compliance is acceptable.”
CarcinogenicityAcceptedBeyond the letter
Rodent carcinogenicity NOAEL exposures below or only slightly above human exposure
Why: Low exposure multiples not a concern given the proposed indication · Serious disease
“Nevertheless, for both rodents, exposure margins obtained at the NOAEL for carcinogenicity are not existing (< 1 x) or rather low (1 – 2 x) with regard to the total concentrations or free concentrations of maribavir based on AUC.”
“Considering the proposed indication, the low exposure multiples should not be a concern.”
Safety marginVerdict not stated
26-week rat NOAEL exposure about 0.1 times total human AUC
“The NOAEL was set at 25 mg/kg/day resulting in exposures below human therapeutic exposures for total (approximately 0.1-times) and free unbound (approximately 0.5-times) maribavir based on AUC.”
Safety marginAcceptedBeyond the letter
High clinical exposures (up to 1200 mg) not reached in nonclinical safety studies
Why: Exposure covered by the 800 mg and 1200 mg clinical studies · Human data
“These Cmax and AUC exposures have not generally been reached in the non-clinical safety studies, and thus, the non-clinical study package provides no support for this wide therapeutic window.”
“However, this exposure is covered by both the 800 mg and 1200 mg phase 2 studies and may therefore be acceptable based on clinical safety data.”
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